Moonlighting Proteins

List of Contributors xv Preface xix About the Editor xxiii Part I Overview of Protein Moonlighting 1 1 What is Protein Moonlighting and Why is it Important? 3 Constance J. Jeffery 1.1 What is Protein Moonlighting? 3 1.2 Why is Moonlighting Important? 5 1.2.1 Many More Proteins Might Moonlight 5 1.2.2 Protein Structure/Evolution 5 1.2.3 Roles in Health and Disease 8 1.2.3.1 Humans 8 1.2.3.2 Bacteria 10 1.3 Current questions 11 1.3.1 How Many More Proteins Moonlight? 11 1.3.2 How Can We Identify Additional Proteins That Moonlight and all the Moonlighting Functions of Proteins? 11 1.3.3 In Developing Novel Therapeutics, How Can We Target the Appropriate Function of a Moonlighting Protein and Not Affect Other Functions of the Protein? 12 1.3.4 How do Moonlighting Proteins get Targeted to More Than One Location in the Cell? 12 1.3.5 What Changes in Expression Patterns Have Occurred to Enable the Protein to be Available in a New Time and Place to Perform a New Function? 12 1.4 Conclusions 13 References 13 2 Exploring Structure–Function Relationships in Moonlighting Proteins 21 Sayoni Das, Ishita Khan, Daisuke Kihara, and Christine Orengo 2.1 Introduction 21 2.2 Multiple Facets of Protein Function 22 2.3 The Protein Structure–Function Paradigm 23 2.4 Computational Approaches for Identifying Moonlighting Proteins 25 2.5 Classification of Moonlighting Proteins 26 2.5.1 Proteins with Distinct Sites for Different Functions in the Same Domain 27 2.5.1.1 α‐Enolase, Streptococcus pneumonia 27 2.5.1.2 Albaflavenone monooxygenase, Streptomyces coelicolor A3(2) 29 2.5.1.3 MAPK1/ERK2, Homo sapiens 30 2.5.2 Proteins with Distinct Sites for Different Functions in More Than One Domain 30 2.5.2.1 Malate synthase, Mycobacterium tuberculosis 31 2.5.2.2 BirA, Escherichia coli 31 2.5.2.3 MRDI, Homo sapiens 33 2.5.3 Proteins Using the Same Residues for Different Functions 33 2.5.3.1 GAPDH E. coli 33 2.5.3.2 Leukotriene A4 hydrolase, Homo sapiens 33 2.5.4 Proteins Using Different Residues in the Same/Overlapping Site for Different Functions 34 2.5.4.1 Phosphoglucose isomerase, Oryctolagus cuniculus, Mus musculus, Homo sapiens 34 2.5.4.2 Aldolase, Plasmodium falciparum 36 2.5.5 Proteins with Different Structural Conformations for Different Functions 36 2.5.5.1 RfaH, E. coli 36 2.6 Conclusions 37 References 39 Part II Proteins Moonlighting in Prokarya 45 3 Overview of Protein Moonlighting in Bacterial Virulence 47 Brian Henderson 3.1 Introduction 47 3.2 The Meaning of Bacterial Virulence and Virulence Factors 47 3.3 Affinity as a Measure of the Biological Importance of Proteins 49 3.4 Moonlighting Bacterial Virulence Proteins 50 3.4.1 Bacterial Proteins Moonlighting as Adhesins 52 3.4.2 Bacterial Moonlighting Proteins That Act as Invasins 59 3.4.3 Bacterial Moonlighting Proteins Involved in Nutrient Acquisition 59 3.4.4 Bacterial Moonlighting Proteins Functioning as Evasins 60 3.4.5 Bacterial Moonlighting Proteins with Toxin‐like Actions 63 3.5 Bacterial Moonlighting Proteins Conclusively Shown to be Virulence Factors 64 3.6 Eukaryotic Moonlighting Proteins That Aid in Bacterial Virulence 66 3.7 Conclusions 67 References 68 4 Moonlighting Proteins as Cross‐Reactive Auto‐Antigens 81 Willem van Eden 4.1 Autoimmunity and Conservation 81 4.2 Immunogenicity of Conserved Proteins 82 4.3 HSP Co‐induction, Food, Microbiota, and T-cell Regulation 84 4.3.1 HSP as Targets for T‐Cell Regulation 85 4.4 The Contribution of Moonlighting Virulence Factors to Immunological Tolerance 87 References 88 Part III Proteins Moonlighting in Bacterial Virulence 93 Part 3.1 Chaperonins: A Family of Proteins with Widespread Virulence Properties 95 5 Chaperonin 60 Paralogs in Mycobacterium tuberculosis and Tubercle Formation 97 Brian Henderson 5.1 Introduction 97 5.2 Tuberculosis and the Tuberculoid Granuloma 97 5.3 Mycobacterial Factors Responsible for Granuloma Formation 98 5.4 Mycobacterium tuberculosis Chaperonin 60 Proteins, Macrophage Function, and Granuloma Formation 100 5.4.1 Mycobacterium tuberculosis has Two Chaperonin 60 Proteins 100 5.4.2 Moonlighting Actions of Mycobacterial Chaperonin 60 Proteins 101 5.4.3 Actions of Mycobacterial Chaperonin 60 Proteins Compatible with the Pathology of Tuberculosis 102 5.4.4 Identification of the Myeloid‐Cell‐Activating Site in M. tuberculosis Chaperonin 60.1 105 5.5 Conclusions 106 References 106 6 Legionella pneumophila Chaperonin 60, an Extra‐ and Intra‐Cellular Moonlighting Virulence‐Related Factor 111 Karla N. Valenzuela‐Valderas, Angela L. Riveroll, Peter Robertson, Lois E. Murray, and Rafael A. Garduno 6.1 Background 111 6.2 HtpB is an Essential Chaperonin with Protein‐folding Activity 112 6.3 Experimental Approaches to Elucidate the Functional Mechanisms of HtpB 112 6.3.1 The Intracellular Signaling Mechanism of HtpB in Yeast 113 6.3.2 Yeast Two‐Hybrid Screens 118 6.4 Secretion Mechanisms Potentially Responsible for Transporting HtpB to Extracytoplasmic Locations 120 6.4.1 Ability of GroEL and HtpB to Associate with Membranes 121 6.4.2 Ongoing Mechanistic Investigations on Chaperonins Secretion 122 6.5 Identifying Functionally Important Amino Acid Positions in HtpB 124 6.5.1 Site‐Directed Mutagenesis 125 6.6 Functional Evolution of HtpB 126 6.7 Concluding Remarks 127 References 129 Part 3.2 Peptidylprolyl Isomerases, Bacterial Virulence, and Targets for Therapy 135 7 An Overview of Peptidylprolyl Isomerases (PPIs) in Bacterial Virulence 137 Brian Henderson 7.1 Introduction 137 7.2 Proline and PPIs 137 7.3 Host PPIs and Responses to Bacteria and Bacterial Toxins 138 7.4 Bacterial PPIs as Virulence Factors 138 7.4.1 Proposed Mechanism of Virulence of Legionella pneumophila Mip 140 7.5 Other Bacterial PPIs Involved in Virulence 140 7.6 Conclusions 142 References 142 Part 3.3 Glyceraldehyde 3‐Phosphate Dehydrogenase (GAPDH): A Multifunctional Virulence Factor 147 8 GAPDH: A Multifunctional Moonlighting Protein in Eukaryotes and Prokaryotes 149 Michael A. Sirover 8.1 Introduction 149 8.2 GAPDH Membrane Function and Bacterial Virulence 150 8.2.1 Bacterial GAPDH Virulence 151 8.2.2 GAPDH and Iron Metabolism in Bacterial Virulence 153 8.3 Role of Nitric Oxide in GAPDH Bacterial Virulence 153 8.3.1 Nitric Oxide in Bacterial Virulence: Evasion of the Immune Response 154 8.3.2 Formation of GAPDHcys‐NO by Bacterial NO Synthases 155 8.3.3 GAPDHcys‐NO in Bacterial Virulence: Induction of Macrophage Apoptosis 155 8.3.4 GAPDHcys‐NO in Bacterial Virulence: Inhibition of Macrophage iNOS Activity 156 8.3.5 GAPDHcys‐NO in Bacterial Virulence: Transnitrosylation to Acceptor Proteins 157 8.4 GAPDH Control of Gene Expression and Bacterial Virulence 158 8.4.1 Bacterial GAPDH Virulence 159 8.5 Discussion 160 Acknowledgements 162 References 162 9 Streptococcus pyogenes GAPDH: A Cell‐Surface Major Virulence Determinant 169 Vijay Pancholi 9.1 Introduction and Early Discovery 169 9.2 GAS GAPDH: A Major Surface Protein with Multiple Binding Activities 170 9.3 AutoADP‐Ribosylation of SDH and Other Post‐Translational Modifications 172 9.4 Implications of the Binding of SDH to Mammalian Proteins for Cell Signaling and Virulence Mechanisms 173 9.5 Surface Export of SDH/GAPDH: A Cause or Effect? 178 9.6 SDH: The GAS Virulence Factor‐Regulating Virulence Factor 180 9.7 Concluding Remarks and Future Perspectives 183 References 183 10 Group B Streptococcus GAPDH and Immune Evasion 195 Paula Ferreira and Patrick Trieu‐Cuot 10.1 The Bacterium GBS 195 10.2 Neonates are More Susceptible to GBS Infection than Adults 195 10.3 IL‐10 Production Facilitates Bacterial Infection 196 10.4 GBS Glyceraldehyde‐3‐Phosphate Dehydrogenase Induces IL‐10 Production 197 10.5 Summary 199 References 200 11 Mycobacterium tuberculosis Cell‐Surface GAPDH Functions as a Transferrin Receptor 205 Vishant M. Boradia, Manoj Raje, and Chaaya Iyengar Raje 11.1 Introduction 205 11.2 Iron Acquisition by Bacteria 206 11.2.1 Heme Uptake 206 11.2.2 Siderophore‐Mediated Uptake 207 11.2.3 Transferrin Iron Acquisition 207 11.3 Iron Acquisition by Intracellular Pathogens 207 11.4 Iron Acquisition by M. tb 208 11.4.1 Heme Uptake 208 11.4.2 Siderophore‐Mediated Iron Acquisition 209 11.4.3 Transferrin‐Mediated Iron Acquisition 209 11.5 Glyceraldehyde‐3‐Phosphate Dehydrogenase (GAPDH) 210 11.6 Macrophage GAPDH and Iron Uptake 210 11.6.1 Regulation 210 11.6.2 Mechanism of Iron Uptake and Efflux 211 11.6.3 Role of Post‐Translational Modifications 211 11.7 Mycobacterial GAPDH and Iron Uptake 212 11.7.1 Regulation 212 11.7.2 Mechanism of Iron Uptake 215 11.7.3 Uptake by Intraphagosomal M. tb 216 11.8 Conclusions and Future Perspectives 216 Acknowledgements 218 References 219 12 GAPDH and Probiotic Organisms 225 Hideki Kinoshita 12.1 Introduction 225 12.2 Probiotics and Safety 225 12.3 Potential Risk of Probiotics 227 12.4 Plasminogen Binding and Enhancement of its Activation 228 12.5 GAPDH as an Adhesin 229 12.6 Binding Regions 232 12.7 Mechanisms of Secretion and Surface Localization 234 12.8 Other Functions 235 12.9 Conclusion 236 References 237 Part 3.4 Cell‐Surface Enolase: A Complex Virulence Factor 245 13 Impact of Streptococcal Enolase in Virulence 247 Marcus Fulde and Simone Bergmann 13.1 Introduction 247 13.2 General Characteristics 248 13.3 Expression and Surface Exposition of Enolase 249 13.4 Streptococcal Enolase as Adhesion Cofactor 252 13.4.1 Enolase as Plasminogen‐Binding Protein 252 13.4.1.1 Plasminogen‐Binding Sites of Streptococcal Enolases 253 13.4.2 Role of Enolase in Plasminogen‐Mediated Bacterial‐Host Cell Adhesion and Internalization 254 13.4.3 Enolase as Plasminogen‐Binding Protein in Non‐Pathogenic Bacteria 255 13.5 Enolase as Pro‐Fibrinolytic Cofactor 256 13.5.1 Degradation of Fibrin Thrombi and Components of the Extracellular Matrix 257 13.6 Streptococcal Enolase as Cariogenic Factor in Dental Disease 258 13.7 Conclusion 258 Acknowledgement 259 References 259 14 Streptococcal Enolase and Immune Evasion 269 Masaya Yamaguchi and Shigetada Kawabata 14.1 Introduction 269 14.2 Localization and Crystal Structure 271 14.3 Multiple Binding Activities of α‐Enolase 273 14.4 Involvement of α‐Enolase in Gene Expression Regulation 276 14.5 Role of Anti‐α‐Enolase Antibodies in Host Immunity 277 14.6 α‐Enolase as Potential Therapeutic Target 279 14.7 Questions Concerning α‐Enolase 281 References 281 15 Borrelia burgdorferi Enolase and Plasminogen Binding 291 Catherine A. Brissette 15.1 Introduction to Lyme Disease 291 15.2 Life Cycle 292 15.3 Borrelia Virulence Factors 292 15.4 Plasminogen Binding by Bacteria 293 15.5 B. burgdorferi and Plasminogen Binding 294 15.6 Enolase 295 15.7 B. burgdorferi Enolase and Plasminogen Binding 297 15.8 Concluding Thoughts 301 Acknowledgements 301 References 301 Part 3.5 Other Glycolytic Enzymes Acting as Virulence Factors 309 16 Triosephosphate Isomerase from Staphylococcus aureus and Plasminogen Receptors on Microbial Pathogens 311 Reiko Ikeda and Tomoe Ichikawa 16.1 Introduction 311 16.2 Identification of Triosephosphate Isomerase on S. aureus as a Molecule that Binds to the Pathogenic Yeast C. neoformans 312 16.2.1 Co‐Cultivation of S. aureus and C. neoformans 312 16.2.2 Identification of Adhesins on S. aureus and C. neoformans 312 16.2.3 Mechanisms of C. neoformans Cell Death 313 16.3 Binding of Triosephosphate Isomerase with Human Plasminogen 314 16.4 Plasminogen‐Binding Proteins on Trichosporon asahii 314 16.5 Plasminogen Receptors on C. neoformans 316 16.6 Conclusions 316 References 317 17 Moonlighting Functions of Bacterial Fructose 1,6‐Bisphosphate Aldolases 321 Neil J. Oldfield, Fariza Shams, Karl G. Wooldridge, and David P.J. Turner 17.1 Introduction 321 17.2 Fructose 1,6‐bisphosphate Aldolase in Metabolism 321 17.3 Surface Localization of Streptococcal Fructose 1,6‐bisphosphate Aldolases 322 17.4 Pneumococcal FBA Adhesin Binds Flamingo Cadherin Receptor 323 17.5 FBA is Required for Optimal Meningococcal Adhesion to Human Cells 324 17.6 Mycobacterium tuberculosis FBA Binds Human Plasminogen 325 17.7 Other Examples of FBAs with Possible Roles in Pathogenesis 326 17.8 Conclusions 327 References 327 Part 3.6 Other Metabolic Enzymes Functioning in Bacterial Virulence 333 18 Pyruvate Dehydrogenase Subunit B and Plasminogen Binding in Mycoplasma 335 Anne Gründel, Kathleen Friedrich, Melanie Pfeiffer, Enno Jacobs, and Roger Dumke 18.1 Introduction 335 18.2 Binding of Human Plasminogen to M. pneumoniae 337 18.3 Localization of PDHB on the Surface of M. pneumoniae Cells 340 18.4 Conclusions 343 References 344 Part 3.7 Miscellaneous Bacterial Moonlighting Virulence Proteins 349 19 Unexpected Interactions of Leptospiral Ef‐Tu and Enolase 351 Natália Salazar and Angela Barbosa 19.1 Leptospira –Host Interactions 351 19.2 Leptospira Ef‐Tu 352 19.3 Leptospira Enolase 353 19.4 Conclusions 354 References 354 20 Mycobacterium tuberculosis Antigen 85 Family Proteins: Mycolyl Transferases and Matrix‐Binding Adhesins 357 Christopher P. Ptak, Chih‐Jung Kuo, and Yung‐Fu Chang 20.1 Introduction 357 20.2 Identification of Antigen 85 358 20.3 Antigen 85 Family Proteins: Mycolyl Transferases 359 20.3.1 Role of the Mycomembrane 359 20.3.2 Ag85 Family of Homologous Proteins 359 20.3.3 Inhibition and Knockouts of Ag85 360 20.4 Antigen 85 Family Proteins: Matrix‐Binding Adhesins 361 20.4.1 Abundance and Location 361 20.4.2 Ag85 a Fibronectin‐Binding Adhesin 362 20.4.3 Ag85 an Elastin‐Binding Adhesin 363 20.4.4 Implication in Disease 364 20.5 Conclusion 365 Acknowledgement 365 References 365 Part 3.8 Bacterial Moonlighting Proteins that Function as Cytokine Binders/Receptors 371 21 Miscellaneous IL‐1β‐Binding Proteins of Aggregatibacter actinomycetemcomitans 373 Riikka Ihalin 21.1 Introduction 373 21.2 A. actinomycetemcomitans Biofilms Sequester IL‐1β 374 21.3 A. actinomycetemcomitans Cells Take in IL‐1β 375 21.3.1 Novel Outer Membrane Lipoprotein of A. actinomycetemcomitans Binds IL‐1β 375 21.3.2 IL‐1β Localizes to the Cytosolic Face of the Inner Membrane and in the Nucleoids of A. actinomycetemcomitans 377 21.3.3 Inner Membrane Protein ATP Synthase Subunit β Binds IL‐1β 377 21.3.4 DNA‐Binding Histone‐Like Protein HU Interacts with IL‐1β 378 21.4 The Potential Effects of IL‐1β on A. actinomycetemcomitans 379 21.4.1 Biofilm Amount Increases and Metabolic Activity Decreases 379 21.4.2 Potential Changes in Gene Expression 380 21.5 Conclusions 381 References 382 Part 3.9 Moonlighting Outside of the Box 387 22 Bacteriophage Moonlighting Proteins in the Control of Bacterial Pathogenicity 389 Janine Z. Bowring, Alberto Marina, José R. Penadés, and Nuria Quiles‐Puchalt 22.1 Introduction 389 22.2 Bacteriophage T4 I‐TevI Homing Endonuclease Functions as a Transcriptional Autorepressor 391 22.3 Capsid Psu Protein of Bacteriophage P4 Functions as a Rho Transcription Antiterminator 394 22.4 Bacteriophage Lytic Enzymes Moonlight as Structural Proteins 398 22.5 Moonlighting Bacteriophage Proteins De‐Repressing Phage‐Inducible Chromosomal Islands 398 22.6 dUTPase, a Metabolic Enzyme with a Moonlighting Signalling Role 401 22.7 Escherichia coli Thioredoxin Protein Moonlights with T7 DNA Polymerase for Enhanced T7 DNA Replication 404 22.8 Discussion 404 References 406 23 Viral Entry Glycoproteins and Viral Immune Evasion 413 Jonathan D. Cook and Jeffrey E. Lee 23.1 Introduction 413 23.2 Enveloped Viral Entry 414 23.3 Moonlighting Activities of Viral Entry Glycoproteins 415 23.3.1 Viral Entry Glycoproteins Moonlighting as Evasins 416 23.3.2 Evading the Complement System 417 23.3.3 Evading Antibody Surveillance 419 23.3.3.1 The Viral Glycan Shield 419 23.3.3.2 Shed Viral Glycoproteins: An Antibody Decoy 421 23.3.3.3 Antigenic Variations in Viral Glycoproteins 421 23.3.3.4 Shed Viral Glycoproteins and Immune Signal Modulation 423 23.3.4 Evading Host Restriction Factors 423 23.3.5 Modulation of Other Immune Pathways 424 23.4 Viral Entry Proteins Moonlighting as Saboteurs of Cellular Pathways 427 23.4.1 Sabotaging Signal Transduction Cascades 427 23.4.2 Host Surface Protein Sabotage 428 23.5 Conclusions 429 References 429 Index 439